This invention relates to an improved process for carrying out the last step in the preparation of the herbicide ethyl xcex1-2-dichloro-5-[4-(difluoro-methyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate, a Meerwein diazotization and arylation reaction.
The herbicide, which has the following structure, 
is disclosed and claimed in U.S. Pat. No. 5,125,958.
In common practice a Meerwein diazotization and arylation reaction is carried out in two steps. First, an arylamine is diazotized in an aqueous solution of e.g., sodium nitrite, and then the solution of diazotized amine is added to a solution of the compound to be arylated. In U.S. Pat. No. 5,125,958 the last step in the preparation of the herbicide involved diazotization of the amine 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1-(5-amino-2-fluoro-4-chlorophenyl)-1H-1,2,4-triazole. However, since it had been found that when one attempted to diazotize this amine in aqueous solution, the 2-fluoro substituent was lost by hydrolysis to the corresponding phenol. Accordingly, the diazotization described in the patent was carried out in the conventional two steps, but in nonaqueous medium, with t-butyl nitrite as the source of the nitrite. The diazotized amine was then added to ethyl acrylate (the arylation) to yield the desired herbicide. While this procedure is satisfactory for laboratory production on a small scale, it is not satisfactory for large scale, commercial production. Not only is the supply of t-butyl nitrite too limited, but large scale production would require handling large quantities of the diazo compound, an undesirably hazardous operation.
Surprisingly, it has now been found that under the proper conditions the diazotization and arylation can be carried out simultaneously, with aqueous sodium nitrite, without loss of the 2-fluoro substituent and in surprisingly good yields.
The diazotization/arylation reaction sequence is as follows: 
As noted above, in common practice the diazonium salt is first prepared and then added to the compound to be arylated. In the process of the invention the hydrochloride salt of the amine A is diazotized with sodium nitrite in the presence of ethyl acrylate, the material to be arylated. The diazonium chloride (D) produced by the diazotization of the amine hydrochloride with sodium nitrite reacts with ethyl acrylate in the presence of a catalytic amount of copper(I) chloride. The reaction is carried out at low temperature in acetone. The use of acetone as the solvent allows the use of sodium nitrite in a minimum of water. Acetone also facilitates the recycling of the copper(I) chloride catalyst. Another advantage of the process is that the fact that the diazotization acrylation reactions are occurring simultaneously minimizes the probability of the diazotization product reacting with itself.
The process starts with the preparation of a solution of the amine A in acetone, preferably in an inert atmosphere, e.g. nitrogen. A useful ratio of acetone to amine is in the range of 10 to 30 equivalents of acetone to one equivalent of amine, preferably 20 to 25 equivalents of acetone to one of amine. The solution may be filtered to remove any insoluble material that may be present. To the amine solution is added, with stirring, a Meerwein arylation catalyst, for example, copper(I) chloride or copper(II) chloride, preferably copper(I) chloride, and, again, an inert atmosphere is preferred. (Stirring is maintained throughout the course of the reaction.) The amount of copper(I) chloride is important in the process of the present invention. If too little is used, the reaction is slower, and the yield of the final product is lower. Too much copper(I) chloride in the reaction mixture results in dechlorination of the final product. Therefore, a useful ratio of copper(I) chloride to amine is in the range of 0.05 to 1.0 equivalent of copper(I) chloride to one equivalent of amine, preferably 0.1 to 0.15 equivalent to one. The reaction mixture is then cooled to below 0xc2x0 C., preferably to about xe2x88x9210xc2x0 C., and the amine salt is prepared by addition of concentrated hydrochloric acid, or anhydrous hydrogen chloride, preferably anhydrous hydrogen chloride added below the surface of the reaction mixture. During the addition the reaction mixture is maintained at a temperature of xe2x88x9220xc2x0 C. to 30xc2x0 C., preferably xe2x88x9210xc2x0 C. to 10xc2x0 C. The preparation of the amine salt requires about 30 to 120 minutes, preferably about 45 to 90 minutes. The amount of ethyl acrylate that is next added to the amine salt slurry is important. A large excess of ethyl acrylate is required to obtain optimum yields from this process. If the excess is reduced, the yield of final product is reduced. A useful ratio of ethyl acrylate to amine has been found to be 5 to 20 equivalents of ethyl acrylate to one equivalent of amine, preferably 10 to 15 equivalents to one. The time needed to add the ethyl acrylate is relatively unimportant. However, the reaction mixture temperature is maintained below 10xc2x0 C. throughout the addition and is controlled to some degree by the addition of the ethyl acrylate. The reaction mixture is then brought to about 0xc2x0 C., and an aqueous solution of sodium nitrite is added to the reaction mixture. This step is a critical step in the process of the present invention. The diazotization/arylation reactions are occurring simultaneously. During the diazotization step water must be kept to a minimum. A large amount of water results in hydrolysis of the diazo intermediate, yielding a phenol by-product. To minimize the production of by-products a useful ratio of sodium nitrite to amine is in the range of 1.0 to 2.0 equivalents of sodium nitrite to one equivalent of amine, preferably 1.4 to 1.7 equivalents to one. To keep the amount of water to a minimum, it is advantageous to use a concentrated aqueous solution of sodium nitrite for the diazotization step. A saturated aqueous solution of sodium nitrite contains about 40% (wt/wt) of sodium nitrite. A useful concentration of the aqueous solution of sodium nitrite is, therefore, about 20% to 40% (wt/wt) sodium nitrite, preferably 35% to 40% sodium nitrite. Reaction mixture temperatures are also important in optimizing the diazotization/arylation reaction. Temperatures above 10xc2x0 C. increase the probability of by-product formation. A useful range of reaction mixture temperatures for the optimization of the process step is xe2x88x9210xc2x0 C. to 20xc2x0 C., preferably 0xc2x0 C. to 10xc2x0 C. The rate of addition of the aqueous sodium nitrite solution is also important in optimizing yield. Fast rates of addition in the process of the present invention result in lower yields of product. The optimum rate of addition requires about 1 to 6 hours, preferably 2 to 3 hours. The addition of the aqueous sodium nitrite solution is done below the surface of the stirred reaction mixture. The reaction mixture is then stirred for a period of 15 to 90 minutes, preferably 20 to 40 minutes, to allow completion of the reaction. At this point crude yields of product in the range of 80-88% are obtained. The purity of the product may be improved by washing, followed by distillation. During the washing step the temperature is maintained at about xe2x88x9210xc2x0 C. to 20xc2x0 C., preferably 5xc2x0 C. to 10xc2x0 C., and in the preferred washing sequence the reaction mixture is washed first with a dilute aqueous acid, for example, 5% hydrochloric acid, then with a dilute aqueous base, for example 5% sodium hydroxide, and finally with a sodium chloride solution. Upon completion of the wash steps, the volatile material in the reaction mixture, i. e., acetone/ethyl acrylate, may be removed at a pot temperature of 30xc2x0 C. to 80xc2x0 C., preferably 40xc2x0 C. to 65xc2x0 C., under a reduced pressure of 20 mm to 70 mm Hg, preferably 45 mm to 55 mm Hg. The removal of volatile material is considered complete when the ethyl acrylate concentration is below about five percent. Ethyl acrylate is known to polymerize under certain conditions. As a precautionary measure, an antioxidant and a free-radical inhibitor are added to the distillation overhead system. There is, however, no evidence that polymerization occurs in the reaction vessel during the reaction, wash steps, or during removal of the volatile material.
For further purification of the product the non-volatile material containing the reaction product may be distilled in a shod path evaporaror or wiped-film still. In order to increase the efficiency of the distillation process, the reaction product may be passed (degassing step) through the still at an evaporator temperature of 100xc2x0 C. to 140xc2x0 C. and a pressure of 10 mm to 20 mm Hg, preferably 120xc2x0 C. to 130xc2x0 C. and a pressure of 13 mm to 18 mm Hg, to remove any remaining ethyl acrylate or other low-boiling materials. The degassed reaction product may then be passed once through the still at an evaporator temperature of 160xc2x0 C. to 180xc2x0 C. and a pressure of 1.0 mm to 5.0 mm Hg, preferably 170xc2x0 C. to 180xc2x0 C. and a pressure of 1.0 mm to 2.0 mm Hg. The non-volatile material from the first pass through the still may then be passed a second time through the still at an evaporator temperature of 160xc2x0 C. to 200xc2x0 C. and a pressure of 0.03 mm to 1.0 mm Hg, preferably 160xc2x0 C. to 180xc2x0 C. and a pressure of 0.03 mm to 0.5 mm Hg. The rate of feed through the still will be governed by the size of the still. It is understood that the conditions for degassing and distillation will vary, depending on the apparatus used. Operation under preferred conditions has given a typical percent yield of distilled ethyl xcex1-2-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate of 75-80% (based on the amount of starting amine); at a purity of about 91% (as determined by high pressure liquid chromatography).